{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:02:59Z","timestamp":1790881379987,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,29]]},"group-title":"Cancer Biology","reference-count":88,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH-NCI","award":["U54CA209988"],"award-info":[{"award-number":["U54CA209988"]}]},{"name":"NIH-NCI","award":["U01CA224012"],"award-info":[{"award-number":["U01CA224012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pancreatic ductal adenocarcinoma (PDAC) progression involves malignant cell state plasticity. Epigenetic changes underlie this plasticity, yet the PDAC\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory landscape remains understudied. To address this, we profiled 33 primary tumors and 7 metastases from 39 patients with single-cell ATAC-seq, paired with 10 single-cell RNA-seq profiles. We found that epigenetic\n                  <jats:italic>GATA6<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  \/\n                  <jats:italic>KRT17<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  co-accessibility identifies a classical-basal subtype-intermediate progenitor state (SIP) associated with better clinical outcomes. SIP cells display limited epigenetic reprogramming from premalignant epithelium and retain gastric-intestinal differentiation reminiscent of neoplastic precursors. Lineages without\n                  <jats:italic>GATA6<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  \/\n                  <jats:italic>KRT17<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  co-accessibility exhibit greater lineage and epithelial-mesenchymal plasticity. Classical PDACs that repress basal gene accessibility activate neural-like progenitor (NRP) and tuft lineage enhancers, whereas basal committed tumors display esophageal transdifferentiation. Compared to SIP, classical-NRP and basal committed tumors have poorer outcomes, and show distinct PD-1\/PD-L1 immune proteomic phenotypes and prognostic myofibroblast epigenetic states, respectively. Our work reveals links between lineage reprogramming, EMT, and epigenetic progression in human PDAC.\n                <\/jats:p>","DOI":"10.64898\/2026.09.28.754674","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:10:16Z","timestamp":1790698216000},"source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2657-8762","authenticated-orcid":false,"given":"Kevin A","family":"Hawthorne","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1499-8417","authenticated-orcid":false,"given":"Jennifer 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OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0352-1859","authenticated-orcid":false,"given":"Ellen M","family":"Langer","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR"},{"name":"Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR"},{"name":"Knight Cancer Institute, Portland, OR"},{"name":"Division of Oncological Sciences, Oregon Health & Science University, Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0874-1482","authenticated-orcid":false,"given":"Trent A","family":"Waugh","sequence":"additional","affiliation":[{"name":"Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan 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